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1.
Science ; 367(6480)2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32079747

RESUMO

Current influenza vaccines only confer protection against homologous viruses. We synthesized pulmonary surfactant (PS)-biomimetic liposomes encapsulating 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), an agonist of the interferon gene inducer STING (stimulator of interferon genes). The adjuvant (PS-GAMP) vigorously augmented influenza vaccine-induced humoral and CD8+ T cell immune responses in mice by simulating the early phase of viral infection without concomitant excess inflammation. Two days after intranasal immunization with PS-GAMP-adjuvanted H1N1 vaccine, strong cross-protection was elicited against distant H1N1 and heterosubtypic H3N2, H5N1, and H7N9 viruses for at least 6 months while maintaining lung-resident memory CD8+ T cells. Adjuvanticity was then validated in ferrets. When alveolar epithelial cells (AECs) lacked Sting or gap junctions were blocked, PS-GAMP-mediated adjuvanticity was substantially abrogated in vivo. Thus, AECs play a pivotal role in configuring heterosubtypic immunity.

2.
Life Sci ; 240: 117138, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31809715

RESUMO

Pyroptosis is a form of cell death mediated by gasdermin D (GSDMD); it is characterised by NLRP3 inflammasome activation, caspase activation, cell membrane pore formation, and the release of interleukin-1ß and interleukin-18. NLRP3 inflammasome activation plays a central role in pyroptosis. Recent research has suggested that NLRP3 inflammasome activation may be involved in the occurrence and development of diabetes mellitus and its associated complications. This finding provided the impetus for us to clarify the significance of pyroptosis in diabetes. In this review, we summarise the current understanding of the molecular mechanisms involved in pyroptosis, as well as recent advances in the role of NLRP3 inflammasome activation and pyroptosis in the development of diabetes and diabetic complications.


Assuntos
Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/genética , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/genética , Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Piroptose/genética , Animais , Complicações do Diabetes/patologia , Diabetes Mellitus/patologia , Humanos , Inflamassomos/efeitos dos fármacos , Piroptose/efeitos dos fármacos
3.
Brain ; 142(9): 2845-2859, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31312839

RESUMO

Mutations in lysosomal genes increase the risk of neurodegenerative diseases, as is the case for Parkinson's disease. Here, we found that pathogenic and protective mutations in arylsulfatase A (ARSA), a gene responsible for metachromatic leukodystrophy, a lysosomal storage disorder, are linked to Parkinson's disease. Plasma ARSA protein levels were changed in Parkinson's disease patients. ARSA deficiency caused increases in α-synuclein aggregation and secretion, and increases in α-synuclein propagation in cells and nematodes. Despite being a lysosomal protein, ARSA directly interacts with α-synuclein in the cytosol. The interaction was more extensive with protective ARSA variant and less with pathogenic ARSA variant than wild-type. ARSA inhibited the in vitro fibrillation of α-synuclein in a dose-dependent manner. Ectopic expression of ARSA reversed the α-synuclein phenotypes in both cell and fly models of synucleinopathy, the effects correlating with the extent of the physical interaction between these molecules. Collectively, these results suggest that ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein.

4.
Inflammation ; 42(5): 1808-1820, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31243649

RESUMO

Hyaluronan (HA) fragments have been proposed to elicit defensive or pro-inflammatory responses in many cell types. For articular chondrocytes in an inflammatory environment, studies have failed to reach consensus on the endogenous production or effects of added HA fragments. The present study was undertaken to resolve this discrepancy. Cultured primary human articular chondrocytes were exposed to the inflammatory cytokine IL-1ß, and then tested for changes in HA content/size in conditioned medium, and for the expression of genes important in HA binding/signaling or metabolism, and in other catabolic/anabolic responses. Changes in gene expression caused by enzymatic degradation of endogenous HA, or addition of exogenous HA fragments, were examined. IL-1ß increased the mRNA levels for HA synthases HAS2/HAS3 and for the HA-binding proteins CD44 and TSG-6. mRNA levels for TLR4 and RHAMM were very low and were little affected by IL-1ß. mRNA levels for catabolic markers were increased, while type II collagen (α1(II)) and aggrecan were decreased. HA concentration in the conditioned medium was increased, but the HA was not degraded. Treatment with recombinant hyaluronidase or addition of low endotoxin HA fragments did not elicit pro-inflammatory responses. Our findings showed that HA fragments were not produced by IL-1ß-stimulated human articular chondrocytes in the absence of other sources of reactive oxygen or nitrogen species, and that exogenous HA fragments from oligosaccharides up to about 40 kDa in molecular mass were not pro-inflammatory agents for human articular chondrocytes, probably due to low expression of TLR4 and RHAMM in these cells.

5.
J Environ Manage ; 241: 53-58, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30981143

RESUMO

Phenol as a semi-volatile organic compound (SVOC) extensively presents in industrial wastewater. Moreover, it is a main compound of tar existing in the vapor phase from biomass pyrolysis or gasification. So far, most of works on the phenol adsorption by activated carbons have been conducted in the liquid phase. However, the adsorption of phenol in the gas phase has not been reported. This work aims to synthesize the hierarchically porous carbons from the unaltered and pelletized rice husk (RH) via a facile pyrolysis followed by the ball-milling-assisted KOH activation. Herein, the silica nanoparticles in RH acted as a self-template to remarkably increase specific surface areas and pores, thereby giving rise to the formation of hierarchically porous carbons, which showed a relatively high adsorption capacity (maximum value: 1919 mg/g) of phenol in the vapor phase. Generally, the process of phenol adsorption onto porous carbons in the gas phase followed with various interactions, including pore filling, electrostatic interaction, hydrophobic effect, and functional groups effect (e.g., π-π interaction). And the pseudo-second-order model could well describe the adsorption kinetic. It is noted that the pelletized RH was more favorable to develop the porous carbons with the hierarchically meso-microporous structures that could enhance the transfer of the phenol molecules via the outer layer and subsequent uptake by the adsorption sites on the inner layer. Further, the SVOC phenol was hard to volatilize under ambient conditions due to its relatively higher boiling point (181.7 °C), so the thermal desorption was a potential way to regenerate the spent activated biochars.


Assuntos
Oryza , Fenol , Adsorção , Fenóis , Porosidade
6.
Cell Mol Immunol ; 16(9): 757-769, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30705387

RESUMO

Proper control of B cell growth and metabolism is crucial for B-cell-mediated immunity, but the underlying molecular mechanisms remain incompletely understood. In this study, Sin1, a key component of mTOR complex 2 (mTORC2), specifically regulates B cell growth and metabolism. Genetic ablation of Sin1 in B cells reduces the cell size at either the transitional stage or upon antigen stimulation and severely impairs metabolism. Sin1 deficiency also severely impairs B-cell proliferation, antibody responses, and anti-viral immunity. At the molecular level, Sin1 controls the expression and stability of the c-Myc protein and maintains the activity of mTORC1 through the Akt-dependent inactivation of GSK3 and TSC1/2, respectively. Therefore, our study reveals a novel and specific role for Sin1 in coordinating the activation of mTORC2 and mTORC1 to control B cell growth and metabolism.

7.
Sci Total Environ ; 646: 1567-1577, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30235641

RESUMO

The activated bio-chars (AB) were successfully synthesized from rice husk by one- and two-step KOH-catalyzed pyrolysis. The two-step pyrolysis can produce the high yields of AB compared to the one-step pyrolysis. Moreover, the yield of AB decreased with the increase of the mass ratio of KOH and char, which had a significant effect on the development of the surface area and porosity of carbon. In particular, the AB derived from the two-step pyrolysis at 750°C (mass ratio of KOH and char was 3) had the highest specific surface area (SBET=2138m2/g) with many micro-porous structures, which was favored for the phenol adsorption. The maximum adsorption capacity of AB2-3-750 reached 201mg/g because of its excellent surface porosity property. The phenol can be efficiently removed from water by only several minutes. The Langmuir model defined well the adsorption isotherm with a high correlation coefficient value, indicating a monolayer adsorption behavior. And the adsorption process defined well with the pseudo-second-order model. The phenol molecules passed into the internal surface via the liquid-film controlled diffusion, so the behavior of phenol adsorption onto the AB was predominantly controlled via the chemisorption. Furthermore, the functional groups on the outer surfaces of AB can attract the phenol molecules onto the internal surfaces via "π-π dispersion interaction" and "donor-acceptor effect".


Assuntos
Carvão Vegetal/química , Hidróxidos/química , Fenol/metabolismo , Compostos de Potássio/química , Adsorção , Modelos Químicos , Oryza , Fenóis
8.
Biomed Res Int ; 2018: 1286480, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30539000

RESUMO

A point mutation of mitochondrial DNA (mtDNA) at nucleotide position 3243 A to G (mt.3243A>G) is involved in many common diseases, including maternally inherited diabetes and deafness (MIDD) and mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes (MELAS). However, the mutant level of mt.3243A>G varies both among individuals and in different organs, tissues, and even cells of single individuals. For detection of this mutation, current methods have limited universality and sensitivity and may be not adequate for a routine clinical test. Here, we develop and evaluate a rapid TaqMan-MGB quantitative real-time PCR (qPCR) method for detecting and quantifying the heteroplasmy level of mt.3243A>G in single-tube analysis. With our method, the sensitivity of detection was as low as 0.1%, but the accuracy of quantification was reliable, down to 4%. All positives could be correctly identified, and the heteroplasmy levels determined by qPCR correlated well with the results from restriction fragment length polymorphism (RFLP) and pyrosequencing assays (r = 0.921~0.973 and 0.972~0.984). In addition, we demonstrated that the urinary sediments, leukocytes, or hair follicles might be ideal templates to detect and quantify the heteroplasmy of mt.3243A>G mutation; however, they should be optimized or retreated for further accurate quantification. Our study should allow rapid and high throughput diagnostic testing and can potentially be used to clarify the association between clinical phenotype and pathogenic mitochondrial mutations derived from various tissues.


Assuntos
DNA Mitocondrial/genética , Mutação/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Taq Polimerase/metabolismo , Adolescente , Adulto , Sequência de Bases , Criança , DNA/genética , Estudos de Viabilidade , Feminino , Fluorescência , Humanos , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Polimorfismo de Fragmento de Restrição/genética , Padrões de Referência , Análise de Regressão , Moldes Genéticos
9.
Neurobiol Dis ; 120: 76-87, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30194047

RESUMO

Leucine-rich repeat kinase 2 (LRRK2) is genetically implicated in both familial and sporadic Parkinson's disease (PD). Moreover, LRRK2 has emerged as a compelling therapeutic target for the treatment of PD. Consequently, there is much interest in understanding LRRK2 and its role in PD pathogenesis. LRRK2 is constitutively phosphorylated on two serines, S910 and S935, that are required for interaction of LRRK2 with members of the 14-3-3 family of scaffolding proteins. Pathogenic LRRK2 missense mutations impair the phosphorylation of LRRK2 at these sites, but whether this contributes to PD pathology is unclear. To better understand how loss of LRRK2 phosphorylation relates to PD pathology, we have studied double knockin mice in which Lrrk2's serine 910 and 935 have both been mutated to alanine and can therefore no longer be phosphorylated. Nigrostriatal PD pathology was assessed in adult mice, aged mice, and mice inoculated with α-synuclein fibrils. Under all paradigms there was evidence of early PD pathology in the striatum of the knockin mice, namely alterations in dopamine regulating proteins and accumulation of α-synuclein. Striatal pathology was accompanied by a significant decrease in the number of astrocytes in the knockin mice. Despite striatal pathology, there was no degeneration of dopamine neurons in the substantia nigra and no evidence of a PD motor phenotype in the knockin mice. Our results suggest that modulation of LRRK2 serine 910 and 935 phosphorylation sites may have implications for dopamine turnover and astrocyte function, but loss of phosphorylation at these residues is not sufficient to induce PD neurodegeneration.


Assuntos
Astrócitos/metabolismo , Corpo Estriado/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Substância Negra/metabolismo , Animais , Astrócitos/patologia , Corpo Estriado/patologia , Feminino , Técnicas de Introdução de Genes , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosforilação/fisiologia , Substância Negra/patologia
10.
Bioresour Technol ; 269: 67-73, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30149256

RESUMO

This paper studied the KOH-catalyzed pyrolysis of rice husk (RH) and its pellet (RHP) at a high temperature (750 °C) for activated bio-carbons production. The mass ratio of KOH and biomass greatly impacted the pyrolysis kinetic and biochar property. The KOH catalysis (mass ratio: 1) reduced significantly the activation energy to 41 kJ/mol. During carbonization with KOH, the in-situ generated K2CO3 tailored the morphology and size of the self-template (SiO2 nanoparticles), giving rise to the chars with the open foam-like porous architectures enrich in micro- and meso-pores. Thus, the KOH activation via one-step pyrolysis could produce the micro-mesoporous carbons (e.g., RH-char 1 and RHP-char 1) with high specific surface areas and high content of oxygen-functionalities. Furthermore, the hierarchical porous carbons have high potential applications in adsorption process and electrochemical energy storage (e.g., supercapacitor) because of their unique physicochemical properties.


Assuntos
Carbono/química , Oryza , Adsorção , Catálise , Dióxido de Silício
11.
Exp Neurobiol ; 27(2): 94-102, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29731675

RESUMO

The hippocampus and olfactory bulb incorporate new neurons migrating from neurogenic regions in the brain. Hippocampal atrophy is evident in numerous neurodegenerative disorders, and altered hippocampal neurogenesis is an early pathological event in Alzheimer's disease. We hypothesized that hippocampal neurogenesis is affected by olfactory stimuli through the neural pathway of olfaction-related memory. In this study, we exposed mice to novel pleasant odors for three weeks and then assessed the number of neurons, non-neuronal cells (mainly glia) and proliferating cells in the hippocampus and olfactory bulb, using the isotropic fractionator method. We found that the odor enrichment significantly increased the neuronal cell numbers in the hippocampus, and promoted cell proliferation and neurogenesis in the olfactory bulb. In contrast, the glial cell numbers remained unchanged in both of the regions. Our results suggest that exposure to novel odor stimuli promotes hippocampal neurogenesis and support the idea that enriched environments may delay the onset or slow down the progression of neurodegenerative disorders.

12.
J Thorac Dis ; 10(3): 1689-1695, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29707322

RESUMO

Background: Due to the non-homogeneity of specimens collected from tuberculosis (TB) suspects, repeated Xpert MTB/RIF (Xpert) may have potential clinical benefits. Incremental cost-effectiveness was analyzed for the second Xpert assay to detect Mycobacterium tuberculosis (Mtb) and rifampicin (RIF) resistance. Methods: Specimens were collected from 1,063 pulmonary TB (PTB) and 398 extrapulmonary TB (EPTB) suspects, who had two Xpert tests sequentially within one week. The specimens were subjected to smear, culture, Xpert and drug susceptibility testing. Incremental cost-effectiveness of the serial Xpert assays was evaluated. Results: Among 813 Xpert-positive TB patients, 755 (92.87%) were identified by the first assay whereas the additional 58 (7.13%) were identified by the second assay. The second Xpert assay had higher incremental yield for smear-negative than for smear-positive specimens (12.07% vs. 1.84%, P<0.001), and higher incremental yield for EPTB than for PTB (10.71% vs. 4.65%, P=0.003). About 94.48% (137/145) of the RIF-resistant patients were identified by the first Xpert assay and 5.52% (8/145) were identified by the second Xpert assay. After the first assay, the incremental cost of performing a second Xpert was huge: US$22.82 vs. US$467.72 (P<0.001) and US$35.02 vs. US$291.87 (P<0.001) for PTB and EPTB, respectively. The incremental cost of performing a second Xpert is lower in smear-negative than in smear-positive group in both PTB and EPTB. Conclusions: One Xpert assay is sufficient for smear-positive cases, and a second Xpert assay is beneficial not only for Mtb detection but also for RIF-resistant diagnosis for smear-negative TB suspects, whereas the incremental cost for the second Xpert is huge.

13.
Artigo em Inglês | MEDLINE | ID: mdl-29760127

RESUMO

Due to the natural resistance of nontuberculous mycobacteria (NTM) to many antibiotics, the treatment of diseases caused by NTM is often long-term but unsuccessful. The main goal of this study was to evaluate the in vitro susceptibilities to clofazimine of 209 isolates consisting of different NTM species isolated in Beijing, China. Furthermore, 47 reference strains were also tested, including 30 rapidly growing mycobacterium (RGM) species and 17 slowly growing mycobacterium (SGM) species. The potential molecular mechanism contributing to clofazimine resistance of NTM was investigated as well. Clofazimine exhibited excellent activity against both reference strains and clinical isolates of different SGM species, and most of the strains had MICs far below 1 µg/ml. Although the majority of the clinical isolates of Mycobacterium abscessus and Mycobacterium fortuitum had MICs higher than 2 µg/ml, 17 out of the 30 reference strains of different RGM species had MICs below 1 µg/ml in vitro According to the MIC distributions, the tentative epidemiological cutoff (ECOFF) values for Mycobacterium kansasii, Mycobacterium avium, and Mycobacterium intracellulare were defined at 0.5 µg/ml, 1 µg/ml, and 2 µg/ml, respectively. Intriguingly, single-direction cross-resistance between bedaquiline- and clofazimine (Cfz)-resistant isolates was observed among the tested NTM species. This study demonstrates that clofazimine had strong activity against most SGM species in vitro, as well as some RGM species. The data provide important insights into the possible clinical application of Cfz to treat NTM infections.


Assuntos
Antibacterianos/farmacologia , Clofazimina/farmacologia , Micobactérias não Tuberculosas/efeitos dos fármacos , Sequência de Aminoácidos , China , Farmacorresistência Bacteriana Múltipla , Humanos , Testes de Sensibilidade Microbiana , Infecções por Micobactéria não Tuberculosa/tratamento farmacológico , Mycobacterium abscessus/efeitos dos fármacos , Complexo Mycobacterium avium/efeitos dos fármacos , Mycobacterium fortuitum/efeitos dos fármacos , Mycobacterium kansasii/efeitos dos fármacos , Micobactérias não Tuberculosas/isolamento & purificação , Alinhamento de Sequência
14.
J Alzheimers Dis ; 62(4): 1777-1787, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29614681

RESUMO

Alzheimer's disease is characterized by abnormal amyloid-ß (Aß) peptide accumulation beginning decades before symptom onset. An effective prophylactic treatment aimed at arresting the amyloidogenic pathway would therefore need to be initiated prior to the occurrence of Aß pathology. The SIGMAR1 gene encodes a molecular chaperone that modulates processing of the amyloid-ß protein precursor (AßPP). Fluvoxamine is a selective serotonin reuptake inhibitor and a potent SIGMAR1 agonist. We therefore hypothesized that fluvoxamine treatment would reduce Aß production and improve cognition. We firstly investigated the impact of SIGMAR1 on AßPP processing, and found that overexpression and knockdown of SIGMAR1 significantly affected γ-secretase activity in SK-N-MC neuronal cells. We then tested the impact of fluvoxamine on Aß production in an amyloidogenic cell model, and found that fluvoxamine significantly reduced Aß production by inhibiting γ-secretase activity. Finally, we assessed the efficacy of long-term treatment (i.e., ∼8 months) of 10 mg/kg/day fluvoxamine in the J20 amyloidogenic mouse model; the treatment was initiated prior to the occurrence of predicted Aß pathology. Physical examination of the animals revealed no overt pathology or change in weight. We conducted a series of behavioral tests to assess learning and memory, and found that the fluvoxamine treatment significantly improved memory function as measured by novel object recognition task. Two other tests revealed no significant change in memory function. In conclusion, fluvoxamine has a clear impact on γ-secretase activity and AßPP processing to generate Aß, and may have a protective effect on cognition in the J20 mice.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Fluvoxamina/farmacologia , Memória/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/genética , Animais , Animais Geneticamente Modificados , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Linhagem Celular Tumoral , Cricetulus , Modelos Animais de Doenças , Feminino , Humanos , Memória/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores sigma/genética , Receptores sigma/metabolismo
15.
EMBO Rep ; 19(5)2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29599149

RESUMO

Aggregation of α-synuclein is a hallmark of Parkinson's disease and dementia with Lewy bodies. We here investigate the relationship between cytosolic Ca2+ and α-synuclein aggregation. Analyses of cell lines and primary culture models of α-synuclein cytopathology reveal an early phase with reduced cytosolic Ca2+ levels followed by a later Ca2+ increase. Aggregated but not monomeric α-synuclein binds to and activates SERCA in vitro, and proximity ligation assays confirm this interaction in cells. The SERCA inhibitor cyclopiazonic acid (CPA) normalises both the initial reduction and the later increase in cytosolic Ca2+ CPA protects the cells against α-synuclein-aggregate stress and improves viability in cell models and in Caenorhabditis elegans in vivo Proximity ligation assays also reveal an increased interaction between α-synuclein aggregates and SERCA in human brains affected by dementia with Lewy bodies. We conclude that α-synuclein aggregates bind SERCA and stimulate its activity. Reducing SERCA activity is neuroprotective, indicating that SERCA and down-stream processes may be therapeutic targets for treating α-synucleinopathies.


Assuntos
Cálcio/química , Cálcio/metabolismo , Citosol/química , Agregados Proteicos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , alfa-Sinucleína/metabolismo , Animais , Encéfalo/patologia , Caenorhabditis elegans , Linhagem Celular , Células Cultivadas , Retículo Endoplasmático/metabolismo , Humanos , Indóis/farmacologia , Corpos de Lewy , Masculino , Camundongos , Doença de Parkinson/patologia , Ratos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores
16.
Artigo em Inglês | MEDLINE | ID: mdl-28739779

RESUMO

Extensively drug-resistant tuberculosis (XDR-TB) is a deadly form of TB that can be incurable due to its extreme drug resistance. In this study, we aimed to explore the in vitro susceptibility to bedaquiline (BDQ), delamanid (DMD), linezolid (LZD), clofazimine (CLO), moxifloxacin (MFX), and gatifloxacin (GAT) of 90 XDR-TB strains isolated from patients in China. We also describe the genetic characteristics of XDR-TB isolates with acquired drug resistance. Resistance to MFX, GAT, LZD, CLO, DMD, and BDQ was found in 82 (91.1%), 76 (84.4%), 5 (5.6%), 5 (5.6%), 4 (4.4%), and 3 (3.3%) isolates among the XDR-TB strains, respectively. The most frequent mutations conferring fluoroquinolone resistance occurred in codon 94 of the gyrA gene (57.8%), and the strains with these mutations (69.2%) were associated with high-level MFX resistance compared to strains with mutations in codon 90 (25.0%) (P < 0.01). All 5 CLO-resistant isolates exhibited ≥4-fold upward shifts in the BDQ MIC, which were attributed to mutations of codons 53 (60.0%) and 157 (20.0%) in the Rv0678 gene. Additionally, mutation in codon 318 of the fbiC gene was identified as the sole mutation related to DMD resistance. In conclusion, our data demonstrate that the XDR-TB strains exhibit a strikingly high proportion of resistance to the current anti-TB drugs, whereas BDQ, DMD, LZD, and CLO exhibit excellent in vitro activity against XDR-TB in the National Clinical Center on TB of China. The extensive cross-resistance between OFX and later-generation fluoroquinolones indicates that MFX and GAT may have difficulty in producing the desired effect for XDR-TB patients.


Assuntos
Antituberculosos/farmacologia , Clofazimina/farmacologia , Diarilquinolinas/farmacologia , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Fluoroquinolonas/farmacologia , Linezolida/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Nitroimidazóis/farmacologia , Oxazóis/farmacologia , Pequim , China , DNA Girase/genética , Farmacorresistência Bacteriana Múltipla , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Gatifloxacina , Humanos , Testes de Sensibilidade Microbiana , Moxifloxacina , Mutação/genética , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação
17.
J Alzheimers Dis Rep ; 1(1): 237-247, 2017 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-30480241

RESUMO

ATP-binding cassette A7 (ABCA7) is a genetic risk factor for late-onset Alzheimer's disease (AD). It belongs to a group of transporter genes that specializes in regulating lipid transport in the periphery as well as in the brain. ABCA7 has been implicated in a number of roles relating to AD pathology, including phagocytic clearance of amyloid-ß peptides. We have discovered that deletion of ABCA7 in mouse causes a dramatic reduction in white adipose tissue (WAT) in female mice. WAT is important in AD context because it is the primary producer of leptin, which is a hormone that is known to modulate AD neuropathology. WAT in male Abca7-/- mice was not altered. The pathological link between ABCA7 and WAT that impacts on AD is unknown. Our transcription analysis revealed that lipin-1 expression was significantly upregulated in female Abca7-/- mice, indicating that ABCA7 affects WAT development. The circulating leptin level was significantly reduced in female Abca7-/- mice without any change in WAT leptin mRNA or protein expression, indicating that ABCA7 does not affect leptin production, but alters the circulating leptin level indirectly by affecting WAT development. Insulin is a key hormone that regulates WAT development, i.e., adipogenesis, and it was significantly reduced in female Abca7-/- mice. These data when put together suggest that ABCA7 plays a role in regulating WAT development and consequently circulating leptin levels, which are known to modulate AD neuropathology.

18.
Acta Neuropathol ; 133(2): 303-319, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27888296

RESUMO

Inflammation is likely a key contributor to the pathogenesis of Parkinson's disease (PD), a progressively debilitating neurodegenerative disease that is accompanied by a pathological accumulation of the α-synuclein protein in a staged manner through the brain. What leads to the accumulation of α-synuclein in PD and how this relates to inflammatory pathways, however, is not entirely clear. Toll-like receptor (TLR) signaling is a major pathway mediating inflammation and, in particular, TLR2 is increasingly being implicated in PD. We have, therefore, examined the expression of TLR2 in postmortem brain tissue from PD patients and matched controls. We confirm that TLR2 is increased in PD brain, and find that levels of TLR2 correlate with the accumulation of pathological α-synuclein. TLR2 was expressed on neurons as well as microglia; however, the neuronal rather than glial expression of TLR2 was significantly increased in PD brain in accordance with disease staging, and TLR2 was strongly localized to α-synuclein positive Lewy bodies. In cell culture, activation of neuronal TLR2 induced an inflammatory response, including the secretion of inflammatory cytokines and microglial-activating chemokines, as well as the production of reactive oxygen species. Moreover, activation of neuronal TLR2 increased levels of endogenous α-synuclein protein, which was in turn associated with increased levels of the autophagy/lysosomal pathway marker p62. Finally, promoting autophagy with rapamycin or pharmacological inhibition of the TLR2 signaling pathway prevented the TLR2-mediated increase in α-synuclein in neuronal cell cultures. These results implicate neuronal TLR2 expression in human PD pathogenesis. In particular, the increased expression of TLR2 on neurons may provide new insight into disease pathogenesis and/or options for therapeutic intervention.


Assuntos
Encéfalo/imunologia , Encéfalo/patologia , Doença de Parkinson/imunologia , Doença de Parkinson/patologia , Receptor 2 Toll-Like/metabolismo , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Feminino , Humanos , Inflamação/imunologia , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo
19.
Langmuir ; 32(36): 9180-7, 2016 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-27548279

RESUMO

Puzzling aspects of the microporous structure of Stöber silica, including inconsistencies in the BET specific surface area and the long measurement time required for N2 adsorption, hinder further research on and potential applications of this material. In this work, Stöber silica samples prepared using systematic and detailed post-treatment methods were characterized by N2 adsorption, scanning electron microscopy, transmission electron microscopy, inductively coupled plasma optical emission spectrometry, elemental analysis, and Fourier transform infrared spectroscopy. We have found that the often overlooked sample preparation conditions may be the main causes that perplex the gas adsorption characterization results of Stöber silica samples. The pore-blocking processes associated with a variety of sample treatment methods are discussed in detail. Strong evidence for the particle growth model and pore-blocking mechanism involving ethoxyl groups, Si species, and condensation of silanols is provided. A remarkable result is that the measurement time is shortened from 1 month in our previous work to 2-3 days for samples with large specific surface areas. A suitable post-treatment condition is recommended to obtain microporous Stöber silica with a short measurement time, including water washing, low temperature drying without a vacuum, and a short storage time.

20.
Exp Neurobiol ; 25(3): 103-12, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27358578

RESUMO

The subgranular zone (SGZ) and subventricular zone (SVZ) are developmental remnants of the germinal regions of the brain, hence they retain the ability to generate neuronal progenitor cells in adult life. Neurogenesis in adult brain has an adaptive function because newly produced neurons can integrate into and modify existing neuronal circuits. In contrast to the SGZ and SVZ, other brain regions have a lower capacity to produce new neurons, and this usually occurs via parenchymal and periventricular cell genesis. Compared to neurogenesis, gliogenesis occurs more prevalently in the adult mammalian brain. Under certain circumstances, interaction occurs between neurogenesis and gliogenesis, facilitating glial cells to transform into neuronal lineage. Therefore, modulating the balance between neurogenesis and gliogenesis may present a new perspective for neurorestoration, especially in diseases associated with altered neurogenesis and/or gliogenesis, cell loss, or disturbed homeostasis of cellular constitution. The present review discusses important neuroanatomical features of adult neurogenesis and gliogenesis, aiming to explore how these processes could be modulated toward functional repair of the adult brain.

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